1 Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, 2 the only effective treatment involves repeated dosing with a single drug, and now drug resistance is a major 3 concern. Schistosomes require aquatic snails for transmission. Mass drug administration alone has proven 4 ineffective at eliminating schistosomiasis. It is now widely accepted that an integrated approach that includes 5 snail control is essential. Yet current snail control strategies are unsustainable, involving toxic chemicals or 6 introduced predators or competitors. New approaches are needed that focus on transmission by snails. 7 Understanding the molecular mechanisms by which snails and schistosomes interact is key for finding new 8 strategies to interrupt transmission. Yet knowledge about molluscan immunology is far from adequate, and 9 decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just 10 a handful of candidate genes and mechanisms. Using genome-wide association studies we recently 11 identified in the genome of Biomphalaria glabrata three genomic regions in which allelic variation strongly 12 affects resistance to Schistosoma mansoni. One of these regions, PB35, is particularly interesting for two 13 reasons. Firstly, PB35 showed the strongest allelic association with resistance of any gene observed to 14 date, and was significant in two independent studies using different populations of parasites and snails. So 15 the gene in this region may be universally important in controlling schistosomes, rather than important in just 16 a particular strain-by-strain combination. There appear to be only 9 or 10 genes in the region, some of which 17 are completely missing on some haplotypes. So Aim 1 is to use PacBio to fully sequence and annotate each 18 haplotype, and then use RNAi to determine which gene is responsible for the GWAS results. Secondly, 19 PB35 is particularly exciting because it maps to the same chromosomal region as a QTL marker for the 20 dramatic difference in resistance between two well-studied strains of snails, BgBS90 and BgM-line. BgBS90 21 is highly resistant to almost all tested strains of S. mansoni, while BgM-line is susceptible, and the difference 22 segregates as a simple, Mendelian trait. Several lines of evidence suggest the gene responsible for the 23 extreme resistance of BgBS90 is in the PB35 region. Aim 2 will test that hypothesis by using repeated 24 backcrossing and marker-assisted selection to swap just the PB35 region between strains, and then test if 25 that reverses their phenotypes. Why BgBS90 snails are so resistant to schistosomes has been the subject of 26 many functional studies. If the gene in PB35 is behind that phenotype, it will be an important discovery. 27 Identifying new resistance genes will substantially advance our knowledge of snail-schistosome 28 immunology. It is also likely that one could someday genetically manipulate natural snail populations to 29 make them less able to transmit schistosomes. Identifying key resistance genes and characterizing their 30 function would be an essential first step toward that goal. 31